The number of new cases of breast cancer has increased by about one percent per year in the United States since the 1940s. For 2007, an estimated 212,000 new cases of invasive breast cancer are expected to occur among women and men in the United States alone. Although breast cancer is currently subject of intense research an estimated 45,000 patients in the United States will still die from this type of tumour in 2007, demonstrating how little is known about the development and treatment of this particular type of cancer. Estrogen stimulates the proliferation of the most common type of human breast cancer that expresses estrogen receptor ? (ER?) via transcriptional gene activation, placing ER? in a key position for the development of breast cancer. Although a significant body of research on ER? has been carried out over the years, the knowledge of its transcriptional mechanisms remains limited. In our preliminary experiments we have discovered a new set of cofactors for ER?, consisting of the nuclear LIM cofactors RING finger LIM domain-binding protein (RLIM) and cofactor of LIM homeodomain transcription factors (CLIM), that associate with and are able to modulate the transcriptional activity of ER? in breast cancer cells. Furthermore, our results show a highly significant correlation of high CLIM expression with ER/PR positive breast cancers in human patients. We hypothesize that LIM cofactors RLIM and CLIM decisively regulate the biological activity of ER?. This proposal sets out to establish the roles of LIM cofactors 1) for the regulation of ER? -mediated transcriptional activity, 2) the regulation of known cofactor complexes recruited by ER? and 3) the significance for human breast cancer as well as for mammary gland development following puberty in mice. Thus, the proposed research will greatly add to the knowledge of ER? regulation with strong implications for the development of breast cancer thereby likely unraveling new strategies for the design of drugs to treat breast cancer patients. PUBLIC HEALTH RELEVANCE: Estrogen receptor ? (ER?) is decisively involved in the development of many human breast cancers. The proposed experiments in this application will identify a set of cofactors for ER? that critically regulates its transcriptional and biological activity, thereby unravelling new mechanisms of ER? regulation. The expected results will lead to novel strategies for the design of drugs against breast cancer.